Oncogenic KRAS effector USP13 promotes metastasis in non-small cell lung cancer through deubiquitinating β-catenin
Yanguan Guo, Jiaxin Tian, Yongjian Guo, Cong Wang, Congcong Chen, Songwang Cai, Wenliang Yu, Binghe Sun, Jin Yan, Zhonghua Li, Jun Fan, Qi Qi, Dongmei Zhang, Weilin Jin, Zichun Hua, Guo Chen
Abstract
-mutant cancers, effective treatments are still lacking for other KRAS-mutant NSCLCs. Thus, identifying a KRAS effector that confers poor prognosis would provide an alternative strategy for the treatment of KRAS-driven cancers. Here, we show that KRAS drives expression of deubiquitinase USP13 through Ras-responsive element-binding protein 1 (RREB1). Elevated USP13 promotes KRAS-mutant NSCLC metastasis, which is associated with poor prognosis in NSCLC patients. Mechanistically, USP13 interacts with and removes the K63-linked polyubiquitination of β-catenin at lysine 508, which enhances the binding between β-catenin and transcription factor TCF4. Importantly, we identify 2-methoxyestradiol as an effective inhibitor for USP13 from a natural compound library, and it could potently suppress the metastasis of KRAS-mutant NSCLC cells in vitro and in vivo. These findings identify USP13 as a therapeutic target for metastatic NSCLC with KRAS mutations.